Predictive Structure-based Guidelines for Identifying Optimal PEGylation Sites within Proteins

 描述（由申请人提供）：我们的目标是开发基于结构的工具，用于鉴定肽/蛋白质内的最佳聚乙二醇化位点，并使用这些工具增强肽/蛋白质的药代动力学性质。我们的中心假设是，最佳聚乙二醇化位点的特征在于所连接的PEG增强肽/蛋白质构象稳定性的能力。我们的理论基础是，不稳定的，未折叠的或错误折叠的， 蛋白质往往是非功能性的并且比折叠蛋白质具有更多的药代动力学问题（即，更易于聚集、更易受蛋白水解的影响，并且更容易被抗体识别）。因此，蛋白质构象稳定性的增加也应该增强蛋白质的药代动力学性质。然而，目前的聚乙二醇化努力缺乏用于增加蛋白质稳定性的预测工具;相反，试错法占主导地位，这经常导致相对于非聚乙二醇化蛋白质的生物活性降低。利用我们对基于PEG的蛋白质稳定化的日益增长的分子水平的理解，我们将开发基于预测结构的工具，用于生成具有增强的药代动力学特性和不减弱的功能的聚乙二醇化肽/蛋白质，从而加速更好的聚乙二醇化蛋白质药物的开发。

 DESCRIPTION (provided by applicant): Our goal is to develop structure-based tools for identifying optimal PEGylation sites within peptides/proteins and to use these tools to enhance peptide/protein pharmacokinetic properties. Our central hypothesis is that optimal PEGylation sites should be characterized by the ability of the attached PEG to enhance peptide/protein conformational stability. Our rationale for this hypothesis is that unstable, unfolded or misfolded proteins tend to be non-functional and have more pharmacokinetic problems than folded proteins (i.e., are more aggregation-prone, more susceptible to proteolysis, and more readily recognized by antibodies). Therefore increases in protein conformational stability should also enhance protein pharmacokinetic properties However, current PEGylation efforts lack predictive tools for increasing protein stability; instead, a trial-and-error approach prevails, which frequenly results in diminished biological activity relative to the non-PEGylated protein. Using our growing molecular-level understanding of PEG-based protein stabilization, we will develop predictive structure-based tools for generating PEGylated peptides/proteins with enhanced pharmacokinetic properties and undiminished function, thereby accelerating the development of better PEGylated protein drugs.